Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury

Tonnus W, Meyer C, Steinebach C, Belavgeni A, von Mässenhausen A, Gonzalez NZ, Maremonti F, Gembardt F, Himmerkus N, Latk M, Locke S, Marschner J, Li W, Short S, Doll S, Ingold I, Proneth B, Daniel C, Kabgani N, Kramann R, Motika S, Hergenrother PJ, Bornstein SR, Hugo C, Becker JU, Amann KU, Anders HJ, Kreisel D, Pratt D, Gütschow M, Conrad M, Linkermann A (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 12

Article Number: 4402

Journal Issue: 1

DOI: 10.1038/s41467-021-24712-6

Abstract

Acute kidney injury (AKI) is morphologically characterized by a synchronized plasma membrane rupture of cells in a specific section of a nephron, referred to as acute tubular necrosis (ATN). Whereas the involvement of necroptosis is well characterized, genetic evidence supporting the contribution of ferroptosis is lacking. Here, we demonstrate that the loss of ferroptosis suppressor protein 1 (Fsp1) or the targeted manipulation of the active center of the selenoprotein glutathione peroxidase 4 (Gpx4cys/-) sensitize kidneys to tubular ferroptosis, resulting in a unique morphological pattern of tubular necrosis. Given the unmet medical need to clinically inhibit AKI, we generated a combined small molecule inhibitor (Nec-1f) that simultaneously targets receptor interacting protein kinase 1 (RIPK1) and ferroptosis in cell lines, in freshly isolated primary kidney tubules and in mouse models of cardiac transplantation and of AKI and improved survival in models of ischemia-reperfusion injury. Based on genetic and pharmacological evidence, we conclude that GPX4 dysfunction hypersensitizes mice to ATN during AKI. Additionally, we introduce Nec-1f, a solid inhibitor of RIPK1 and weak inhibitor of ferroptosis.

Authors with CRIS profile

Christoph Daniel Department of Nephropathology Kerstin Ute Amann Professur für Nephropathologie

Involved external institutions

Universitätsklinikum Carl Gustav Carus Dresden DE Germany (DE) Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE) Washington University US United States (USA) (US) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE) Universitätsklinikum Köln DE Germany (DE) Universitätsklinikum Aachen (UKA) DE Germany (DE) University of Illinois at Urbana-Champaign US United States (USA) (US) University of Ottawa CA Canada (CA) Klinikum der Universität München DE Germany (DE) Christian-Albrechts-Universität zu Kiel DE Germany (DE)

How to cite

APA:

Tonnus, W., Meyer, C., Steinebach, C., Belavgeni, A., von Mässenhausen, A., Gonzalez, N.Z.,... Linkermann, A. (2021). Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury. Nature Communications, 12(1). https://doi.org/10.1038/s41467-021-24712-6

MLA:

Tonnus, Wulf, et al. "Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury." Nature Communications 12.1 (2021).

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